Mucopolysaccharidosis Type 4

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Retrieved

2021-01-23

Source

Orphanet

Trials

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Genes

GALNS, GLB1, RMRP, COL2A1, COMP, TRPV4, GOLGB1, CRTAP, SHOX, TAPT1, GNPTG, P3H1, FKBP14, TRAPPC2B, SPAM1, SLC13A1, ACAN, TRAPPC2, RPL10, ARSB, NEK1, IDS, HYAL1, FLNB, FGFR3, SLC26A2, COL10A1, PLF

Drugs

Allogeneic multi-virus specific T lymphocytes targeting BK virus, cytomegalovirus, human herpesvirus-6, Epstein Barr virus and adenovirus, Elosulfase alfa ( VIMIZIM ), N-terminal hexaglutamine-tagged recombinant human N-acetylgalactosamine-6-sulfate sulfatase, adeno-associated virus serotype 9 vector containing human n-acetylgalactosamine-6-sulfate sulfatase gene, haematopoietic stem cells and blood progenitors umbilical cord-derived expanded with (1R, 4R)-N1-(2-benzyl-7-(2-methyl-2H-tetrazol-5-yl)-9H-pyrimido[4,5-b]indol-4-yl)cyclohexane-1,4-diamine dihydrobromide dihydrate

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A rare lysosomal storage disease characterized by mild to severe spondylo-epiphyso-metaphyseal dysplasia, manifesting with disproportionate short stature (short neck and trunk), joint laxity, pectus carinatum, genum valgum, abnormal gait, tracheal narrowing, spinal abnormalities (kyphosis and scoliosis), respiratory impairment and valvular heart disease.

Clinical description

Clinically, the two forms of MPS, IVA and IVB, have similar skeletal manifestations; however, MPS IVA has a more severe phenotype. MPS IVA is generally diagnosed during the second year of life. Progressive skeletal and joint deformities lead to impairment in walking and daily activities, and include platyspondyly, kyphosis, scoliosis, pectus carinatum, genu valgum, long bone deformities, and joint hyperlaxity (neck, hands, fingers, hips, knees). A rapidly progressive growth failure, with arrest at around 3-5 years of age in severe cases, results in short stature. Potential nervous complications are secondary to skeletal deformations. From the age of 2 to 5 years, hypoplasia of the odontoid vertebra combined with joint hyperlaxity leads to an instability at the level of the first two cervical vertebrae, with a risk of spinal cord compression. Facial dysmorphism includes prominent forehead, large mandible, and short neck. Respiratory impairment, with heavy restriction of lung capacity, susceptibility to pneumonia, and tracheal obstruction/narrowing, is often indicated by life-threatening sleep apnea, cor pulmonale or anesthetic complications. Extra-skeletal manifestations include hepatomegaly, valvulopathies, hearing loss, corneal clouding and dental hypoplasia. Intelligence is normal. Patients typically have low endurance, debilitating fatigue, and pain. Many patients become wheelchair-dependent in their second decade.

Etiology

The dysfunction and dysplasia is a result of body-wide accumulation of gylcosaminoglycans (GAGs). MPS IVA is due to deficiency in the enzyme N-acetylgalactosamine-6-sulfate sulfatase (GALNS, 16q24.3) required for degradation of keratin sulfate (KS) and chondroitin 6-sulfate. MPS IVB is due to deficiency in beta-galactosidase (GLB1, 3p22.3) required for KS degradation.

Diagnostic methods

Preliminary investigations may include urinary analysis of GAGs; however, total urinary GAG level overlaps between MPS IV patients and age-matched controls. Urine KS and blood KS should be measured. Definitive diagnosis is by demonstration of enzymatic deficiency in plasma, serum, leukocytes or fibroblasts.

Differential diagnosis

Differential diagnosis includes MPS I, II, VI, and VII, spondyloepiphyseal dysplasia, Legg-Calve-Perthes disease, and GM1 gangliosidosis type 3 for MPS IVB.

Antenatal diagnosis

Where the genetic mutation has previously been identified in a family member, prenatal diagnosis is possible through molecular analysis or enzyme measurements in trophoblasts or amniocytes.

Genetic counseling

The pattern of inheritance is autosomal recessive in both forms and genetic counseling should be offered to affected families. The risk of disease transmission is 25% where both parents are unaffected carriers.

Management and treatment

The treatment remains symptomatic (prosthesis, surgery, neck consolidation by vertebral fusion, tracheal vascular reconstruction for near-fatal tracheal obstruction, walking aids or wheelchair). Non-invasive assessment of airway obstruction at an early stage is critical. General anesthesia may be problematic due to intubation difficulties. Imaging of the cervical spine is commonly required. Clinical therapies include hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT), both of which lead to the partial restoration of the clinical phenotype but are not reported to improve skeletal manifestations. ERT with elosulfas alfa is approved for MPS IVA and may be associated with increased endurance and pulmonary function, and reduced urinary excretion of KS. HSCT has been used on over 30 MPS IVA patients, however, further studies are required to evaluate therapeutic efficacy. In MPS IVB, management and treatment remains supportive and surgical.

Prognosis

The common causes of mortality are airway compromise and heart disease. Prognosis depends on disease severity and quality of care. Left untreated, MPS IVA patients do not generally survive beyond the third decade of life; with appropriate management, patients may survive beyond the age of 50 with some surviving over 70 years of age.